Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents. The analyses are based on 8609 repeated observations from 3098 participants aged 2-16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification. The PRS was associated with BMI (beta estimate 95% confidence interval (95%-CI) = 0.33 0.30, 0.37, r  = 0.11, p value = 7.9 × 10 ) and WC (beta 95%-CI = 0.36 0.32, 0.40, r  = 0.09, p value = 1.8 × 10 ). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta 95%-CI = 0.40 0.34, 0.45) in comparison to children from central Europe (beta 95%-CI = 0.29 0.23, 0.34), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta 95%-CI = 0.48 0.38, 0.59) in comparison to children of parents with a high level of education (beta 95%-CI = 0.30 0.26, 0.34), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta 95%-CI interaction = -0.02 -0.04,-0.01) and shorter screen times (beta 95%-CI interaction = 0.02 0.00, 0.03). Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.